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Pilot randomised controlled trial of self-delivered transcutaneous vagus nerve stimulation (tVNS) combined with digital cognitive training (BrainHQ) in mild cognitive impairment (MCI)

The combination of tVNS and high-intensity cognitive training is hypothesised to create a synergistic effect, where the tVNS-mediated release of neuromodulators enhances task-specific plasticity driven by the cognitive exercises. This pilot RCT aims to assess the safety, tolerability, and feasibility of this combined, self-administered intervention.

• Is the self-delivery of active transcutaneous vagus nerve stimulation (tVNS) combined with digital cognitive training (BrainHQ) safe, tolerable, and feasible for use in individuals with Mild Cognitive Impairment (MCI)?
• Does active tVNS combined with BrainHQ enhance cognitive function outcomes (memory, executive function) in people with MCI at 12 weeks and 6-month follow-up, compared to sham tVNS combined with BrainHQ?
• What are the neurophysiological and mechanistic correlates (f-NIRS, heart rate variability, inflammatory markers) associated with active tVNS combined with BrainHQ in people with MCI?

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Supervisors

Dr Ali Ali (ali.ali@sheffield.ac.uk)    

Professor Arshad Majid (arshad.majid@sheffield.ac.uk)

Abstract and methodology

The primary aims of this pilot RCT are to investigate whether self-delivered transcutaneous vagus nerve stimulation (tVNS) combined with digital brain training (BrainHQ) is safe, tolerable, and feasible for use in people with Mild Cognitive Impairment (MCI). Specifically, we will:

• Establish criteria for safety (monitoring adverse events and SAEs) and tolerability (assessing symptom severity via Likert scales)
• Evaluate feasibility metrics, including recruitment rate, participant adherence to the 12-week intervention schedule, and retention rate at the 6-month follow-up
• Explore signals of effect on clinical outcome measures, including global and domain-specific cognitive function, and functional outcomes
• Explore mechanistic effects, including changes in functional connectivity (f-NIRS) Heart Rate Variability (HRV) and inflammatory biomarker profiles, to inform the proposed mechanisms of action for future studies

Masters students will assist in participant recruitment and data collection. Activities include conducting screening and obtaining informed written consent, recording socio-demographic data, and administering clinical outcome measures such as the ACE III, AVLT, and FAQ. Students will receive training in complex techniques: measuring Heart Rate Variability (HRV) using the POLAR H10 monitor and operating the Lumo f-NIRS device for cortical activation assessments. They also manage weekly check-ins to monitor safety and tolerability using aphasia-friendly tools.

The VNS-COG pilot aims to establish the safety, tolerability, and feasibility of tVNS combined with BrainHQ in Mild Cognitive Impairment. Primary outcomes monitor Adverse ¾Ã²Ý¸£Àû and adherence metrics (e.g., recruitment rate and retention), and will be presented descriptively. Exploratory secondary outcomes will evaluate signals of effect on cognition (ACE III, AVLT) and mechanistic markers (HRV, f-NIRS). The Masters students role would include assisting with descriptive analysis of primary outcomes and conducting thematic analysis of qualitative interview data from participants and carers.

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

Training would be provided on the following in the run up to starting on the study:

• Obtaining Informed Written Consent and conducting eligibility checks.
• Administering outcome measure assessments, including cognitive batteries (ACE III, AVLT, STT, FAQ).
• Use of the Lumo f-NIRS device for cortical activation assessments and the POLAR H10 heart rate monitor for measuring Heart Rate Variability (HRV).
• Conducting weekly check-ins, including using aphasia-friendly symptom reporting sheets (with pictures and visual scales) to monitor safety and tolerability.
• Thematic analysis (and/or narrative review) for qualitative data obtained from participant/carer interviews.
• Demonstration/practice of using the tVNS device and the BrainHQ Computerised Cognitive Training (CCT).

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval needed

Identifying cognitive impairments in people with a spinal cord injury

Can we use automated cognitive assessment to identify cognitive impairment in spinal cord injury?

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Supervisors

Dr Simon Bell (s.m.bell@sheffield.ac.uk)    

Dr Dan Blackburn (d.blackburn@sheffield.ac.uk)

Abstract and methodology

Aims and objectives

• Determine the best method for identifying cognitive impairment in people with spinal cord injury
• Determine the views of people living with spinal cord injury and health care professionals that work with those with spinal cord injury preferences for automated or in person cognitive assessment
• Identify if a generic large language model can classify both cognitive and mood scores in spinal cord injury patients

Methodology

The student will conduct face to face interviews with patients with a spinal cord injury at The Princess Royal Spinal Cord Injuries Centre at Northern General Hospital. They will then analyse findings to determine suitability of tools, cognitive domains affected, and consider the use of novel tools to screen for cognitive impairment.

There are currently no guidelines or national standards on screening tools for cognitive impairment in this group.

The results from this project may help to identify tools that can be used to detect cognitive impairment in this group; either through developing new tools or validating already established tools in other conditions, such as the Edinburgh Cognitive and Behaviour Amyotrophic Lateral Sclerosis Screen (ECAS), which is designed assessing cognitive impairment in patients with ALS who may have limited hand motor function.

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

• Good Clinical Practice course
• MOCA training course

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval needed.

Assessing the acceptability of CognoStroke in clinical enviroments

Can automated cognitive assessment be performed effectively in the post stroke setting

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Supervisors

Dr Simon Bell (s.m.bell@sheffield.ac.uk)    

Dr Dan Blackburn (d.blackburn@sheffield.ac.uk)

Abstract and methodology

Aims and objectives

• Identify the opportunities and challenges of using CognoStroke in TIA and follow up clinics.
• Determine what is the best timing for assessment of cognitive function after stroke
• Determine SS attitudes towards Artificial intelligence and automated cognitive assessment
• Identify which elements of the CognoStroke system identify cognitive and mood impairment best post-stroke

Methodology

The student will work closely with the stroke research team and perform the CognoStroke assessment in different clinical settings. They will perform the Montreal Cognitive Assessment (MOCA) and interview SS on their attitudes towards using automated cognitive assessment.

The student will contribute data towards research papers and conference publications. They will be expected to identify patients attitudes toward automated cognitive assessment and the best place to perform this.

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

• Good Clinical Practice course
• MOCA training course

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval obtained already

Measuring brain activity during cognitive tasks in patients with dementia: an fNIRS investigation

Can functional near infrared spectroscopy detect dementia from brain activity recordings during verbal fluency tasks?

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Supervisors

Dr Dan Blackburn (d.blackburn@sheffield.ac.uk)    

Miss Caitlin Illingworth (chillingworth1@sheffield.ac.uk)

Abstract and methodology

Aims

To evaluate the feasibility of combing cognitive assessments with a non-invasive, wearable neuroimaging device to detect signs of cognitive impairment.

Objectives

• To recruit and record the brain activity and performance of 10 patients with mild cognitive impairment or Dementia and 10 healthy controls
• Statistically compare the brain activity seen in patients with that of healthy-age matched controls

The student will 

• be responsible for recruiting patients from the STH memory clinic to take part in the project.
• help to record the brain activity of patients and healthy controls using the LUMO fNIRS device
• analyse the brain activity using MATLAB scripts developed by the supervisors
• analyse task performance to identify more appropriate measures of cognitive impairment

As part of the project, the student will also aid in a systematic review of the literature surrounding functional brain imaging and dementia across language backgrounds

From this work, we will be able to analyse the real time brain activity of patients with dementia during common clinical cognitive tasks. The student will contribute towards a larger project looking to determine unique neural markers of dementia.

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

Students will be taught how to use a high-density fNIRS device to record brain activity, and gain familiarity with data analysis packages such as MATLAB and R. 

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval obtained already.

Integrating the assessment of real world mobility into a platform trial in multiple sclerosis

Is it feasible and acceptable to monitor real world walking within a platform study of multiple sclerosis patients?

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Supervisors

Dr Gavin Brittain (gavin.brittain@sheffield.ac.uk)

Dr Ellen Buckley (e.e.buckley@sheffield.ac.uk)

Abstract and methodology

Aims

To evaluate the feasibility and acceptability of incorporating real-world digital mobility monitoring into a platform clinical study for people with Multiple Sclerosis (MS).

Objectives

• To determine the proportion of participants providing useable wearable data meeting predefined wear-time thresholds.
• To assess participant acceptability and willingness to engage in long-term mobility monitoring using questionnaires.
• To describe baseline real-world mobility of the OCTOPUS MS cohort using digital mobility outcomes (DMOs) derived from a lumbar-worn sensor.
• To explore relationships between DMOs and conventional clinical or functional measures collected within the platform study.

Methods

The student will recruit Multiple Sclerosis (MS) participants attending the OCTOPUS platform study into MoStrAct and facilitate the longitudinal collection of 7 day real world mobility monitoring using a lumbar worn sensor to generate digital mobility outcomes (DMOs). The student will conduct acceptability questionnaires with participants. Training will be provided to enable the student to conduct the assessments.
Analysis of the wearable device via the Mobgap (www.mobilise-d.eu) pipeline will be conducted for the student but training will be offered to enable statistical analysis.

Outcomes

• Assess the feasibility and acceptability of digital mobility assessment as a measurement tool in a clinical trial
• Characterise the cohort’s mobility at baseline via DMOs

It is expected that the collection of real world mobility monitoring within a platform study will be feasible, and acceptable to patients. These outcomes will be assessed by the percentage of useable data which meets a previously defined minimum wear time threshold (12 hours of 3 days from 7), the acceptability questionnaire responses. The cohorts mobility will be described in terms of DMOs which cover the participants amount (i.e. step count, duration) and gait (speed, rhythm, variability) as per the Mobgap analysis pipeline.

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

• Application of lumbar worn inertial measurement units
• Opportunity for training in an alternative statistical software (R/python)
• Interdisciplinary skills (between technical and clinical teams)
• Training in clinical outcome measures

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval obtained already.

Assessing a block-and-replace gene therapy approach to restore NOTCH3 function in CADASIL vascular smooth muscle cells

Can a dual-action block-and-replace plasmid effectively suppress mutant NOTCH3 and restore wild-type expression in CADASIL vascular smooth muscle cells (VSMCs)?

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Supervisors

Professor Arshad Majid (arshad.majid@sheffield.ac.uk)    

Dr Favour Felix-Ilemhenbhio (f.felix-ilemhenbhio@sheffield.ac.uk)

Abstract and methodology

Aim

To assess the therapeutic potential of a block-and-replace gene therapy strategy to correct NOTCH3-related dysfunction in CADASIL-VSMCs.

Objectives

• Transfect CADASIL-VSMCs with the block-and-replace plasmid and verify expression.
• Quantify NOTCH3 transcript suppression and replacement using qPCR.
• Evaluate protein restoration by western blotting.
• Assess phenotypic recovery through microscopy and contractile marker analysis.

Method

The project will employ CADASIL and control human VSMCs transfected with a pre-validated block-and-replace plasmid. qPCR will quantify NOTCH3 transcript changes, and western blotting will determine protein restoration, including markers such as ACTA2 and CNN1. Fluorescence microscopy will be used to assess transfection efficiency and morphological recovery. All experiments will follow established protocols and quality controls to ensure reproducibility.

Timeline

• Transfection of iPSC-derived VSMCs with block-and-replace: January – February
• Quantification of NOTCH3 mRNA (RT-qPCR) and protein (Western blot): March – April
• Functional assays for proliferation and migration: May – June
• Thesis write-up: May – July

These findings will support the feasibility of dual-action gene therapy for CADASIL and contribute preliminary data toward translational validation in vivo.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training or teaching

The student will receive hands-on training in molecular biology and cell culture, including aseptic technique, transfection, RNA and protein quantification, and fluorescence imaging. They will also gain experience in quantitative data analysis (Excel, GraphPad Prism) and scientific writing. Regular lab meetings will provide exposure to experimental design, troubleshooting, and data interpretation in a translational neuroscience context.

Ethics requirements

Secondary data or tissue samples: UREC or NHS REC ethics approval already received for the intended research project